Schiff bases of 2-aminoindole showing hepatoprotective activity

 

(57) Abstract:

The essence of the invention: derivatives of 2-aminoindole f-ly I, where R1is lower alkyl, phenyl, benzyl, Rr2is phenyl, substituted phenyl, hetaryl, R3-alkyl, omega-substituted alkyl. Reagent 1: hydrochloride 2-aminoindole. Reagent 2: aromatic or heterocyclic aldehyde. Reaction conditions: when heated. table 2.

The invention relates to new chemical compounds, particularly to derivatives of 2-aminoindole that exhibit hepatoprotective activity and can find application in medical practice.

Known structural analogues of the claimed compounds [1]. however, information about their hepatoprotective activity.

At present in our country in medical practice as a hepatoprotective tools use zelibor preparation containing an amount of levanidov out, milk Thistle fruit, used in the treatment of hepatitis and cirrhosis [2] also Known drug Essentiale (Germany, Nattermann), legalon (Germany, Kars (Bulgaria), LIV-52 (India), which apply for chronic hepatitis, cirrhosis, toxic liver damage. Essentiale is a set of "essential" (required) FOSFA is et a complex of plant extracts.

However, these known means are used as hepatoprotectors, have several disadvantages. LIV-52 and Essentiale with long-term use causes increased fatty dystrophy, zelibor has a relatively low efficiency. The drawbacks include also the fact that acute toxic liver damage they do not reduce the cytolysis of hepatocytes.

Recently all of the above drugs, except Essentiale, attributed mainly to the choleretic drugs.

At the same time, according to who in the last 10 years all over the world has increased substantially the number of diseases of the hepatobiliary system. According to epidemiological services in our country each year, sick viral and toxic hepatitis in average 400-500 people per 100 thousand population.

In this regard, the search and creation of new domestic hepatoprotective funds is an important public health problem.

The aim of the invention are derivatives of 2-aminoindole showing hepatoprotective activity.

This goal is achieved is not described previously Schiff bases of 2-aminoindole General formula

< / BR>
where

R1lower alkyl, pawlewski hepatoprotective activity.

These compounds get in a known manner, namely, the interaction of hydrochloride 2-aminoindole General formula

< / BR>
with aromatic or heterocyclic aldehydes in the presence of a solvent or fusion. The data of elemental analysis, melting points of the synthesized compounds and the parameters of their IR, UV spectra are presented in table 1.

The method of obtaining the compounds according to the invention is illustrated by the following examples.

Example 1. Obtain 1-benzyl-2-[benzylidene)amino] -3-methyl-indole (compound 1). of 1.36 g(0,005 mol) of the hydrochloride of 1-benzyl-3-methyl-2-aminoindole, 40 ml of absolute ethanol and 0.5 ml (0.005 mole) of benzaldehyde is boiled for 2 hours the precipitation is filtered off, washed with 2-3 ml of chilled absolute ethanol and dried. After recrystallization from absolute ethanol 0,81 g (60% of theory.) 1-benzyl-2-[(benzylidene)amino]-3-methylindole (1). So pl. 102-103oC. Found: C 85,18; H 6,46; N 8,50% C23H20N2. Calculated: C 85,15; H 6,21; 8350 N% UV spectrummax(lg)% 268,1 (4,32; 393,4 (4,06) nm.

Similarly, the compounds 2-9 (table 1).

Example 2. Obtain 1,3-dimethyl-2-[(4-hydroxy-3,5-di-tert-butyl)-benzyliden] aminoindole (compound 13 ). The mixture ,41, (0,005 mol) of sodium acetate melted at a temperature of 200-205oC for 5 minutes, after which the melt is cooled to 60-70oTo add benzene, filtered, nerastvorim in benzene residue, and the solution chromatographic on a small column of silica gel, elwira benzene. The eluate containing the desired substance 13, evaporated in vacuo, the residue triturated in hexane and filtered. Yellow crystals. Yield 65% so pl. 114-115oC. Found: C 79,46; H 8,67; N 6,95% C25H32N2O. Calculated: C 79,79; H 8,51; N 7,45% IR range: 3590, 1660 cm-1.

Similarly, the compounds 10-12, 14 (table 1)

Evaluation of the hepatoprotective effect was carried out on a model of acute toxic hepatitis in mice-males and a model of chronic toxic hepatitis in rats-males. As Comparators used domestic hepatoprotector zelibor and Essentiale (Germany). Compound and the Comparators were introduced into the starch mucus intraperitoneally. In each experimental group were 6 animals. In the control group and the groups with Comparators were, on average, 100 mice (table 2).

1. Series. Evaluation of the hepatoprotective effect was carried out on outbred mice-males weighing 18-20 g on the model of the CFAA carbon (CCl4in the dose of 1.5 DL250. Compound was administered intraperitoneally 1 h before and 24 h after injection of CCl4at a dose of 50 mg/kg Hepatoprotective effect was evaluated by survival of mice for 4 days. The degree hepatoprotective effect was expressed as a percentage (the ratio of the number of survivors to the total number of animals used).

In the research it was found that after a single dose intraperitoneally control mice (118 mice) CCl4at a dose of 0.005 ml/g body weight of a 50% solution in liquid paraffin survival of animals on the 4 day equal to an average of 182% (table 2).

The Comparators Essentiale and zelibor several reduced the mortality of mice after poisoning CCl4. Thus, survival in the application Essentiale was 222% and celebra 255% which was not significantly different from the control model.

At the same time, the number of investigated compounds increased the survival rate of mice after poisoning CCl4on average more than two times in comparison with control groups. This indicates the presence of hepatoprotective activity of the test compounds exceeding the activity of Comparators zelibor and Essentiale (table 2). Most hepatoprotective effect was observed , hepatoprotective activity.

Thus, as a result of tests it is established that acute poisoning CCl4the claimed compounds possess detoxifying activity, reducing the mortality of animals in a single hepatotropic defeat, and some of them can be considered as promising compounds with high hepatoprotective activity that exceeds the Comparators and with low toxicity.

Schiff bases of 2-aminoindole General formula

< / BR>
where R1lower alkyl, benzyl, phenyl;

R2phenyl, substituted phenyl, hetaryl;

R3alkyl, substituted alkyl,

showing hepatoprotective activity.

 

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